| First Author | Cho J | Year | 2011 |
| Journal | Circ Res | Volume | 108 |
| Issue | 4 | Pages | 478-89 |
| PubMed ID | 21233455 | Mgi Jnum | J:183494 |
| Mgi Id | MGI:5318819 | Doi | 10.1161/CIRCRESAHA.110.229658 |
| Citation | Cho J, et al. (2011) Myocardial injection with GSK-3beta-overexpressing bone marrow-derived mesenchymal stem cells attenuates cardiac dysfunction after myocardial infarction. Circ Res 108(4):478-89 |
| abstractText | RATIONALE: Glycogen synthase kinase (GSK)-3beta upregulates cardiac genes in bone marrow-derived mesenchymal stem cells (MSCs) in vitro. Ex vivo modification of signaling mechanisms in MSCs may improve the efficiency of cardiac cell-based therapy (CBT). Objective: To test the effect of GSK-3beta on the efficiency of CBT with MSCs after myocardial infarction (MI). METHODS AND RESULTS: MSCs overexpressing either GSK-3beta (GSK-3beta-MSCs), LacZ (LacZ-MSCs), or saline was injected into the heart after coronary ligation. A significant improvement in the mortality and left ventricular (LV) function was observed at 12 weeks in GSK-3beta-MSC-injected mice compared with in LacZ-MSC- or saline-injected mice. MI size and LV remodeling were reduced in GSK-3beta-MSC-injected mice compared with in LacZ-MSC- or saline-injected ones. GSK-3beta increased survival and increased cardiomyocyte differentiation of MSCs, as evidenced by activation of an Nkx2.5-LacZ reporter and upregulation of troponin T. Injection of GSK-3beta-MSCs induced Ki67-positive myocytes and c-Kit-positive cells, suggesting that GSK-3beta-MSCs upregulate cardiac progenitor cells. GSK-3beta-MSCs also increased capillary density and upregulated paracrine factors, including vascular endothelial growth factor A (Vegfa). Injection of GSK-3beta-MSCs in which Vegfa had been knocked down abolished the increase in survival and capillary density. However, the decrease in MI size and LV remodeling and the improvement of LV function were still observed in MI mice injected with GSK-3beta-MSCs without Vegfa. CONCLUSIONS: GSK-3beta significantly improves the efficiency of CBT with MSCs in the post-MI heart. GSK-3beta not only increases survival of MSCs but also induces cardiomyocyte differentiation and angiogenesis through Vegfa-dependent and -independent mechanisms. |
